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Regimen in Recurrent Endometrial Cancer Challenged: TAP Not Superior to Less-Toxic, Two-Drug Therapy

Maurie Markman, MD
Published: Tuesday, Jul 03, 2012
Dr. Harald zur Hausen

Harald zur Hausen, MD, who won a Nobel Prize in 2008 for elucidating the human papilloma viruses that cause cervical cancer, calls for vaccinating young males and females in a speech at the Society of Gynecologic Oncology conference.

Without question, the most important study discussed at the SGO meeting was the long and eagerly awaited results of the phase III randomized Gynecologic Oncology Group (GOG) trial that compared the GOG standard of paclitaxel, doxorubicin, and cisplatin (TAP) with the widely recognized clinical community standard of carboplatin plus paclitaxel as primary chemotherapeutic management of metastatic or recurrent endometrial cancer.1

A total of 1381 patients were treated on this trial from 2003 to 2009. The study revealed the equivalence (or in statistical terminology, the noninferiority) in outcome for the carboplatin/paclitaxel regimen compared with the three-drug combination. The median progression-free survival in this study was 14 months in both trial arms, with median overall survival found to be 32 months for carboplatin/ paclitaxel versus 38 months for TAP, respectively (hazard ratio, 1.01). As anticipated, the two- drug combination was associated with a more favorable toxicity profile (less thrombocytopenia, vomiting, diarrhea, metabolic side effects) compared with the TAP program.

While the intent of this commentary is to highlight study results presented at the annual SGO meeting, it is appropriate to acknowledge the controversy surrounding the conduct of this trial, specifically the complex decision-making process that led the GOG to consider this three-drug combination to be its standard treatment regimen in this clinical setting. Hopefully, the study outcome will result in the discontinuation of the use of this more toxic strategy in the routine management of metastatic or recurrent endometrial cancer.

Here are several other studies with noteworthy findings:

Cervical

Tirapazamine Fails to Enhance Standard

A GOG phase III trial compared the standard-of-care program of weekly cisplatin plus external beam radiation (chemoradiation) with cisplatin plus tirapazamine and external beam radiation as primary therapy for stages IB2, IIA, IIIB, and IVA cervical carcinoma.2 It had been hypothesized that tirapazamine might sensitize hypoxic cells to the effects of the cisplatin and radiation. While the study was discontinued slightly early (after 402 patients were randomized) due to an issue with drug supply, the trial failed to reveal any impact of the experimental regimen on either progression-free or overall survival, compared with the control arm. Of relevance, this study failed to support the concept that sensitization of the hypoxic cell population can favorably impact outcome in cervical cancer.

Female pelvic anatomy

Illustration courtesy of Alan Hoofring/Don Bliss/National Cancer Institute

Erlotinib Combination Shows Promise

A provocative phase II trial from the Brazilian National Cancer Institute examined the combination of erlotinib plus cisplatin and radiation in the treatment of previously untreated locally advanced cervical cancer.3 Previous preclinical work had revealed that the epidermal growth factor receptor (EGFR) is commonly expressed in cervical cancer, and frequently overexpressed. In this noncomparative study, 34 of the 36 evaluable patients (94%) achieved a clinical complete response. This regimen appears worthy of future investigation in a phase III randomized trial compared with the gold standard of concurrent cisplatin plus radiation in this clinical setting.

Endometrial

Bevacizumab Therapy Draws Responses

In a phase II trial examining the novel combination of bevacizumab plus temsirolimus as therapy for recurrent or persistent endometrial cancer, investigators in the GOG treated a total of 53 patients, of whom 12 experienced a response, including one complete response.4 The median progression-free survival of the population was 5.6 months, with a median overall survival of 17 months. This study was based on preclinical data revealing that the PTEN tumor suppressor gene is commonly inactivated in endometrial cancer. Further, prior studies had demonstrated clinical activity for bevacizumab in this clinical setting. The objective response rate observed in this population of fairly heavily pretreated patients suggests this regimen is worthy of further investigation in endometrial cancer.


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